Safety, reactogenicity, and immunogenicity of MTBVAC in infants: a phase 2a randomised, double-blind, dose-defining trial in a TB endemic setting.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-03-17 DOI:10.1016/j.ebiom.2025.105628

Michele Tameris, Virginie Rozot, Claire Imbratta, Hennie Geldenhuys, Simon C Mendelsohn, Angelique Kany Kany Luabeya, Justin Shenje, Nicolette Tredoux, Michelle Fisher, Humphrey Mulenga, Nicole Bilek, Carly Young, Ashley Veldsman, Natasja Botes, Jelle Thole, Bernard Fritzell, Rajat Mukherjee, Ingrid Murillo Jelsbak, Esteban Rodriguez, Eugenia Puentes, Juana Doce, Dessislava Marinova, Jesús Gonzalo-Asensio, Nacho Aguilo, Carlos Martin, Thomas J Scriba, Mark Hatherill

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引用次数: 0

Abstract

Background: Safer and more effective tuberculosis (TB) vaccines than Bacille Calmette Guérin (BCG) are needed. We evaluated the safety, reactogenicity, and immunogenicity of three dose levels of the live-attenuated Mycobacterium tuberculosis (Mtb) vaccine, MTBVAC, compared to BCG, in South African infants.

Methods: Healthy, HIV-unexposed, BCG-naïve infants were randomised to receive a single intradermal dose of BCG (2.5 × 10⁵ CFU, n = 24) or MTBVAC (2.5 × 10⁴, 2.5 × 10⁵, or 2.5 × 10⁶ CFU, each n = 25). Safety endpoints were solicited systemic, solicited injection site, and unsolicited adverse events (AE), and serious AE (SAE). Immunogenicity was measured using interferon-γ release assay (IGRA) and whole blood intracellular cytokine staining assay. Follow-up was 12 months post-vaccination.

Findings: Ninety-nine infants were enrolled between 18 February 2019 and 08 March 2021. Seventy-eight infants experienced reactogenicity AE (all mild except one grade 2 erythema). Induration, swelling, and erythema were more frequent as MTBVAC dose increased. All reactogenicity events were less frequent in infants receiving MTBVAC 2.5 × 10⁵ CFU compared with BCG. Twelve infants (three BCG and nine MTBVAC recipients) experienced 14 vaccine-unrelated SAE, including one death due to bronchopneumonia (MTBVAC recipient). Eight infants were treated for unconfirmed pulmonary TB (four BCG and four MTBVAC 2.5 × 10⁴ CFU recipients); one BCG recipient was treated for unconfirmed TB meningitis. MTBVAC was immunogenic at all 3 doses, inducing predominantly Th1-cytokine-expressing CD4 T cells, which peaked at Day 56. The 2.5 × 10⁵ and 2.5 × 10⁶ CFU MTBVAC doses induced similar response magnitudes and were more immunogenic than BCG. Day 56 IGRA conversion was observed in 61 (87.4%) infants receiving any MTBVAC dose, but only 28 (42.4%) remained positive by Day 365.

Interpretation: MTBVAC appeared safe, well-tolerated, and immunogenic at doses between 2.5 × 10⁴ and 2.5 × 10⁶ CFU in South African infants. The 2.5 × 10⁵ CFU MTBVAC dose, being less reactogenic and more immunogenic than BCG, was selected for a multi-centre, phase 3 trial.

Funding: This trial was funded by the European and Developing Countries Clinical Trials Partnership (EDCTP).

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mbvac在婴儿中的安全性、反应性和免疫原性：在结核病流行环境中进行的一项2a期随机、双盲、剂量确定试验

背景：需要比卡介苗更安全、更有效的结核病（TB）疫苗。我们在南非婴儿中评估了三种剂量水平的减毒结核分枝杆菌活疫苗（Mtb）（mbvac）与卡介苗的安全性、反应原性和免疫原性。方法：健康、未暴露hiv的BCG-naïve婴儿随机接受单次皮内卡介苗（2.5 × 105 CFU, n = 24）或MTBVAC （2.5 × 104、2.5 × 105或2.5 × 106 CFU，各n = 25）。安全终点包括系统、注射部位、非主动不良事件（AE）和严重不良事件（SAE）。免疫原性采用干扰素γ释放法（IGRA）和全血细胞内细胞因子染色法测定。随访时间为接种疫苗后12个月。研究结果：在2019年2月18日至2021年3月8日期间入组了99名婴儿。78名婴儿出现了反应性AE（除1例2级红斑外均为轻度）。随着MTBVAC剂量的增加，硬化、肿胀和红斑更加频繁。与卡介苗相比，接受mtvac 2.5 × 105 CFU的婴儿的所有反应性事件发生率较低。12名婴儿（3名卡介苗接种者和9名MTBVAC接种者）经历了14例与疫苗无关的SAE，包括1例因支气管肺炎死亡（MTBVAC接种者）。8名婴儿接受未经确诊的肺结核治疗（4名卡介苗和4名MTBVAC 2.5 × 104 CFU接受者）；一名卡介苗接受者接受了未经证实的结核性脑膜炎治疗。MTBVAC在所有3个剂量下都具有免疫原性，主要诱导表达th1细胞因子的CD4 T细胞，在第56天达到峰值。2.5 × 105和2.5 × 106 CFU剂量MTBVAC诱导的应答量相似，且免疫原性高于卡介苗。第56天，接受任何剂量MTBVAC的61名婴儿（87.4%）观察到IGRA转化，但只有28名（42.4%）在第365天保持阳性。在南非婴儿中，剂量在2.5 × 104和2.5 × 106 CFU之间时，MTBVAC似乎是安全的、耐受性良好的和免疫原性的。选择2.5 × 105 CFU MTBVAC剂量进行多中心3期试验，该剂量比卡介苗的反应性更低，免疫原性更强。资助：该试验由欧洲和发展中国家临床试验伙伴关系（EDCTP）资助。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.